Pharmaceutical compositions

ABSTRACT

A dry powder layering process for preparing pharmaceutical compositions of the leukotriene antagonist zafirlukast. The process forms coated beads suitable for sprinkling on to food and drink.

This application is a 371 of PCT IG898/03765 filed Dec. 15, 1998.

The present invention relates to pharmaceutical compositions and inparticular to pharmaceutical compositions containing the leukotrieneantagonist zafirlukast. The invention also relates to processes forpreparing such compositions and to their use in treating diseaseconditions mediated by leukotriene antagonists.

Zafirlukast is an orally administered leukotriene antagonist marketedunder the trade mark ‘ACCOLATE’. Zafirlukast is marketed for thetreatment, including prophylactic treatment, of asthma and is presentedas a tablet formulation containing 20 mg or 40 mg active ingredient.Asthma and related conditions are of particular concern in children andin the elderly. However, these patient groups have particulardifficulties in swallowing medicaments in tablet form. The presentinvention provides a formulation of zafirlukast that permits easieradministration and in particular should be of especial benefit forpaediatric and geriatic patients.

Zafirlukast, which has the chemical nameN-[4-[5-(cyclopentyloxycarbonyl)amino-1-methylindol-3-ylmethyl]-3-methoxybenzoyl]-2-methylbenzene, is knownin a number of physical forms. U.S. Pat. No. 4,859,692 discloses thiscompound as Example 105. U.S. Pat. No. 5,319,097 discloses that thiscompound can exist in more than one physical form and that thesephysical forms have differing stabilities and bioavailabilities. Form Ais disclosed as amorphous and as having good bioavailability. It isfurther disclosed that Form A tends to convert into Form B in thepresence of water and that this is disadvantageous. It is unattractiveto develop a formulation containing a mixture of physical forms withdifferent bioavailabilities, especially where one form is physicallyunstable, because the effective dose of the compound can not becontrolled properly. Form B is disclosed as a crystalline monohydratewith a defined X-ray powder diffraction pattern and a defined infra-redspectrum. Form X is disclosed as crystalline with a defined X-ray powderdiffraction pattern.

U.S. Pat. No. 5,294,636 discloses particular formulations of Form X.Example 4 describes a tablet formulation prepared by a wet granulationprocess followed by drying, milling, blending and compression. Examples2 and 3 describe pharmaceutical compositions of Form X that are suitablefor administration by metered dose inhaler. Example 5 describes themicronisation of Form X to produce a powder which was extruded to formsoft pellets; these pellets were free flowing and relatively dust freeand, on shearing, broke back down to the original particle sizedistribution indicating that the pellets were suitable for inhalationaluse.

U.S. Pat. No. 5,319,097 discloses particular formulations of Form A.Example 3 describes a tablet formulation prepared by a wet granulationprocess followed by drying, milling, blending and compression. Aparticular feature of this Example is the presence ofpolyvinylpyrrolidone (also known as povidone). Example 5 describes acapsule formulation, a beadlet (spheroid) formulation and a powderformulation. The beadlet formulation is prepared by spraying an aqueousdispersion of polyvinylpyrrolidone and zafirlukast (in equal amounts) onto sugar spheres. This is an example of a suspension layering process,as zafirlukast, at the exemplified concentration would be partiallysoluble in the dispersion.

Pellets (also known as beadlets, spheroids, coated non-pareils, coatedbeads, coated seeds or granules) wherein a central core is surrounded bya layer containing drug may be prepared in a number of different ways.One method is to spray a solution of the drug optionally containingpharmaceutically acceptable ingredients on to the core material. Anothermethod is to spray a suspension of the drug optionally containingpharmaceutically acceptable ingredients on to the core or seed materialas was described in U.S. Pat. No. 5,319,097. A third method is to applythe drug and other pharmaceutically acceptable ingredients in the drystate. This third method is known as ‘dry powder layering’. Usually drypowder layering requires the presence of water alone, or water with anaqueous binder or other solvent to facilitate the binding of the druglayer to the core material.

As stated hereinabove, zafirlukast exists in a number of physical formsand it is known that unwanted interconversion between certain forms canoccur, especially in the presence of water. The three layering methodsoutlined above normally require water (as solvent, as the suspensionmedium, or to facilitate binding). Therefore, Applicants faced a problemin preparing pellets containing zafirlukast in particular in theamorphous form as none of the three methods was especially promising forpreparing layered pellets suitable for pharmaceutical use. Unexpectedly,however, Applicants found that the pellets prepared by the dry powderlayering method were stable and the physical forms of zafirlukast didnot interconvert during the preparation and processing (includingconditions of elevated temperatures and humidity) of the formulation.The preferred pellets of this invention are stable, non-friable andresist attrition. In particular, there is a tendency for any amorphousmaterial (for example Form A) to convert to a crystalline form duringprocessing conditions—as crystalline forms are generally the more stableforms. As stated hereinabove, it is unattractive to develop aformulation containing a mixture of physical forms with differentbioavailabilities, especially where one form is physically unstable,because the effective dose of the compound can not be controlledproperly.

Accordingly, the present invention provides a process for preparing apharmaceutical composition which comprises applying amorphouszafirlukast and a binding agent and optionally other pharmaceuticallyacceptable ingredients to a plurality of cores to form layered pelletsin which zafirlukast is present essentially in amorphous form. Amorphouszafirlukast is in dry form, appropriate for dry powder layering,immediately before the composition process.

Preferably the binding agent is an aqueous binding agent and inparticular is water alone or water with other solvents.

Optionally a further binding agent may be present in the drug layer toassist the binding to the core material and to improve the strength ofthe pellets. Such additional binding agents may be any known to theperson skilled in the art for this purpose. Preferred binding agents arepolyvinylpyrrolidone and hydroxypropylmethylcellulose; of thesepolyvinylpyrrolidone is most preferred.

The cores are typically rotated or tumbled in a container to whichamorphous zafirlukast and binding agent, optionally with otherpharmaceutically acceptable ingredients, are added. The zafirlukast andbinding agent are typically kept separate until they are added to thecontainer; they are added to the container in a common feed orpreferably in separate feeds. The separate feeds are generallysimultaneous although the binding agent feed may commence slightlybefore the zafirlukast feed and may end slightly after the zafirlukastfeed. As stated hereinabove, the function of the binding agent is tofacilitate the binding of zafirlukast (and any pharmaceuticallyacceptable ingredients) to the core. The pharmaceutical ingredients maybe introduced to the container with the zafirlukast feed or with thebinder feed or may be divided, selectively, into both feeds as theskilled person would understand. In general powders are fed into thecontainer together and aqueous ingredients for example water are fed inseparately. It is preferred that any aqueous feed is water or, if theaqueous feed contains other ingredients, it is in the form of a solutionand not in the form of a suspension.

The nature of the central core of each pellet is not critical providedthat it dissolves in aqueous media. Typically the central core materialis a sugar sphere or non-pareil wherein the main ingredients are sugar,such as sucrose, and starch. Such sugar spheres or non-pareils arecommercially available in a number of diameters under the trade marks‘Nu-core’ and ‘Nu-pareil’. Diameters available include 35-40 mesh(425-500 microns), 30-35 mesh (500-600 microns), 25-30 mesh (600-725microns), 20-25 mesh (710-850 microns), 18-20 mesh (850-1000 microns),16-20 mesh (850-1180 microns) and 14-18 mesh (1000-1400 microns). Theseare prepared from crystalline sucrose which is coated using sugar syrupand starch powder. In an alternative the central core is a sugar-freematerial, for example sorbitol, or microcrystalline cellulose; suchcores are prepared in an analogous manner to sugar spheres. The coreswould not usually contain zafirlukast but this is a possibility. Theperson skilled in the art will select the diameter of particles that ismost appropriate considering the depth of surrounding layer that isintended and the desired diameter of the final pellet. Applicants preferto use sugar spheres of 500-850 microns for example 30-35 mesh or 25-30mesh.

Conventional pharmaceutical ingredients may be included in the processesof this invention. Examples of such pharmaceutical ingredients includebulking agents such as sugar, sorbitol and starch; binding agents suchas polyvinylpyrrolidone and hydroxypropylmethylcellulose; disintegrantssuch as starch, croscarmellose sodium, sodium starch glycollate (A andB) and crospovidone; colourants such as titanium dioxide; flavouringagents; taste enhancers; sweeteners such as aspartame; preservatives;anti-oxidants; chelating agents; and surfactants. The binding agents areuseful to assist binding to the core, to improve the strength of thepellet, and to aid the coating of the pellets with a further layer, ifthis is desired. Polyvinylpyrrolidone is available in various grades,known to those skilled in the art as K values. It is preferred to useGrades 29-32.

Typical pharmaceutical ingredients added in the processes of thisinvention include confectioner's sugar, starch and polyvinylpyrrolidone.

The ratio of ingredients may be varied, with regard to the desired dose,size and weight, as known to the skilled person. Suitably the ratio oflayer to core is in the range 1:0.3 to 1:3.0 (w/w), more suitably in therange 1:1 to 1:2 (w/w). The ration of the zafirlukast to otheringredients in the layer is suitably in the range 1:1 to 1:10 (w/w),more suitably in the range 1:1 to 1:6 (w/w).

The dry powder layering process of this invention may be convenientlyperformed in any machine known to be suitable by those skilled in theart. For example the process may be performed in a rotary granulator,such as those sold by Glatt under the trade names Glatt GPCG-1, GlattGPCG-5 and Glatt GPCG-60. [Handbook of Pharmaceutical GranulationTechnology, ed. Dilip M. Parikh, published by Marcel Dekker Inc., 1997,page 291]. These granulators essentially consist of a fluidized beddryer with the bottom of the product bowl consisting of a moveable androtatable disc. The bowl contains ports from which the powder andaqueous binder are fed to the material in the bowl. Typical processingtemperature/conditions for the layering phase, for the GPCG-60 apparatusare as follows: inlet air temperature: 30-40° C.; outlet airtemperature: 25-40° C.; rotor speed 390 rpm; povidone solution flowrate: 100 gmin⁻¹; powder flow rate: 400 gmin⁻¹; processing time: 100minutes.

The layered pellets are then dried at an elevated temperature, forexample 30-60° C. preferably about 45° C., in the container.

These pellets comprise zafirlukast, essentially in amorphous form: thatis substantially free of other physical forms of zafirlukast (forexample as determined by X-ray diffraction data) preferably at least 90%by weight of zafirlukast is amorphous, more preferably 95% for exampleat least 96%, 97%, 98% or 99% is amorphous.

In another aspect, the present invention provides a pharmaceuticalcomposition which comprises a plurality of pellets each of said pelletscomprising:

a) a core; and

b) a layer surrounding said core which layer contains amorphouszafirlukast substantially free of other physical forms,

c) and optionally other pharmaceutically acceptable ingredients.

Preferred pharmaceutical compositions of this invention are thosedescribed hereinabove with reference to the process of this invention.

Preferably the layer surrounding the core comprisespolyvinylpyrrolidone, more preferably wherein the amount ofpolyvinylpyrrolidone is not more than 50% by weight of the amount ofzafirlukast, more preferably still wherein the amount ofpolyvinylpyrrolidone is in the range of 5-30% by weight of the amount ofzafirlukast and in particular is about 10% by weight.

In a preferred aspect the process of the invention comprises separatefeeds, one including amorphous zafirlukast and the other not includingzafirlukast for example including aqueous polyvinylpyrrolidone. Thenon-zafirlukast feed, for example including aqueouspolyvinylpyrrolidone, may be continued after the feed of zafirlukast toprovide a coating layer on the pellets. This coating layer acts as aseal (a ‘seal coat’) and protects the pellets against attrition andfriability, thereby maintaining the integrity of the formulation.

Thus, in a further aspect the present invention provides apharmaceutical composition which comprises a plurality of pellets eachof said pellets comprising:

a) a core;

b) a first layer surrounding said core which layer contains amorphouszafirlukast substantially free of other physical forms, preferablycontains polyvinylpyrrolidone and optionally contains otherpharmaceutically acceptable ingredients; and

c) a second coating layer which does not contain zafirlukast.

In a further aspect, the pharmaceutical compositions of the presentinvention may be coated with a conventional coating layer for protectionof the pellets or to provide sustained release pellets by application ofa conventional sustained release coating such as ‘Surelease’ (a trademark of Colorcon), ‘Aquacoat’ ( a trade mark of FMC) or ‘Eudragit’ ( atrade mark of Huls) which, in general, are cellulose derivatives such ashydroxypropylmethylcellulose or ethylcellulose or are methacrylic acidpolymers. The sustained release coating may be applied using theapparatus described hereinabove or may be applied in a rotarygranulator. The sustained release coating provides a generally uniformand constant rate of release over an extended period of time achieving astable and desired blood (plasma) level of zafirlukast. The pellets maybe substantially uniform or may vary in thickness and composition of thecoating layer as well as in diameter.

Thus, in a further aspect the present invention provides apharmaceutical composition which comprises a plurality of pellets eachof said pellets comprising:

a) a core;

b) a first layer surrounding said core which layer contains amorphouszafirlukast substantially free of other physical forms, preferablycontains polyvinylpyrrolidone and optionally contains otherpharmaceutically acceptable ingredients; and

c) a second coating layer which does not contain zafirlukast and whichprovides sustained release zafirlukast.

In one embodiment, the non-zafirlukast containing feed may be terminatedsimultaneously with the zafirlukast containing feed and the sustainedrelease layer is applied subsequently. In another embodiment, thenon-zafirlukast containing feed is continued after the zafirlukast feedto provide a ‘seal coat’ and the sustained release layer is appliedsubsequently.

Thus, a further aspect of this invention provides a pharmaceuticalcomposition which comprises a plurality of pellets each of said pelletscomprising:

a) a core;

b) a first layer surrounding said core which layer contains amorphouszafirlukast, polyvinylpyrrolidone and optionally other pharmaceuticallyacceptable ingredients;

c) a second layer which does not contain zafirlukast; and

d) a further layer which does not contain zafirlukast and which providessustained release.

The pellets of the present invention typically range in size from 100microns to 2 mm. Favourably they range in size from 200-1500 microns andpreferably are in the range 400-1200 microns. Preferably the pellets areapproximately uniform size and shape.

The pellets are normally sprinkled on to, or into, food or drink foreasy consumption by the patient, but need not be taken with food ordrink. The dose to be administered to the patient will depend on thecondition being treated, the severity of that condition, the age andweight of the patient and the physician's personal preferences. Ingeneral the dose to be administered will be in the range of 0.1 mg/Kg to10 mg/Kg, for example 0.2 mg/Kg to 5 mg/Kg, more particularly 0.5 mg/Kgto 2 mg/Kg.

In another aspect the present invention provides a method of treatingpatients in need thereof with a pharmaceutical composition according tothe present invention which composition contains an effective amount ofzafirlukast.

The pellets are packaged so that a defined dose of zafirlukast isadministered, for example the pellets may be packaged in a sachet, in acapsule or in a metered delivery device. In one aspect a sachet ispreferred wherein the patient tears open the sachet and sprinkles thepellets on to his or her food or drink. In another aspect a capsule ispreferred; one example of such a capsule is that wherein the capsule isconsumable and dissolves/breaks open having been taken orally by thepatient. Another, more preferred example of a capsule is wherein thecapsule is not intended to be consumed and the patient breaks open thecapsule and sprinkles the pellets on to his or her food or drink.Examples of suitable sachets, consumable capsules (such as gelatincapsules) and non-consumable capsules (such as plastic) are known topersons skilled in the art. The dose of zafirlukast delivered in asachet, capsule or metered delivery device may be varied as desired.Typically, 5-40 mg of zafirlukast is delivered in each unit dose, forexample 10 mg, 20 mg or 40 mg of zafirlukast per capsule. The amount (byweight) of zafirlukast in the pellets may also be varied as desired; forexample 100 mg weight of pellets may contain either 10 mg, 20 mg or 40mg of zafirlukast.

The following Examples and data serve to illustrate the invention:

EXAMPLE 1

A 5% w/w solution of polyvinylpyrrolidone (150 g) in purified water USP(2850 ml) was made in a stainless steel vessel and mixed untildissolved. Sugar spheres (1000 g; mesh size 20-25) were placed into arotor processor product container (I.E. Glatt GPCG-1) and thetemperature was taken to 37° C. The polyvinylpyrrolidone solution wassprayed into the container at about 10 gmin⁻¹ at 37° C. Simultaneously,zafirlukast (100 g) was hand fed through an inlet into the productcontainer at a rate of 10 gmin⁻¹. The addition of thepolyvinylpyrrolidone solution was continued for 6 minutes after theaddition of zafirlukast finished to provide a seal coat.

The resultant pellets were dried in the product container by raising theinlet air temperature to 45° C.

The pellets were encapsulated in size #2 hard gelatin capsules using anautomatic encapsulator (I.E. Zanasi AZ/5) to a target fill weight ofapproximately 100 mg with 10% load of zafirlukast.

EXAMPLES 2-8

In a similar manner to that of Example 1, the following Examples wereprepared. In these Examples, zafirlukast, starch and confectioner'ssugar were charged to a blender (I.E. PK V-blender), blended and addedvia a powder feeder (rather than being fed by hand). The pellets weredried in the range 37-55° C.

In some Examples, the Glatt GPCG-1 was replaced by a Glatt GPCG-5 orGlatt GPCG-60 rotor processor container and the encapsulator was an H&Kencapsulator.

Example 2 3 4 5 6 7 8 Zafirlukast 10.00 10.00 10.00 10.00 10.00 10.0010.00 Starch, NF 10.00  4.20  7.20  7.20  7.20  7.20  7.20Confectioner's Sugar 46.67 19.13 32.80 32.80 32.80 32.80 32.80Polyvinylpyrrolidone  2.99  0.96  1.39  1.28  0.67  0.67  0.67 USP SugarSpheres 66.67 50.00 48.86 50.00 49.33 49.33 (30/35 mesh) Sugar Spheres99.50  0.00  0.00  0.00  0.00  0.00  0.00 (20/25 mesh) Purified Water,USP 56.72 23.04 33.38 33.38 16.57 16.67 13.84

Dissolution Studies

Initial dissolution studies, using 1% sodium dodecyl sulfate, onunencapsulated pellets showed satisfactory, rapid dissolution.

Stability Studies

The unencapsulated and encapsulated pellets of Example 7 were studiedfor 180 days at 25° C., 50° C. and at 40° C. (Relative Humidity 80%).X-Ray diffraction data showed no peaks—this indicated unchangedamorphous material with no observable conversion to crystallinematerial. This compares favourably with the results of the tablets ofExample 4, Table 1 of U.S. Pat. No. 5,319,097. In that Table, 87%, 91%and 82% conversion to Form B (monohydrate) was recorded at 40° C.(Relative Humidity 80%) over 1, 2 and 3 months respectively.

EXAMPLES 9-24

Sustained Release Coated Pellets

Talc or magnesium stearate was dispersed in purified water using ahomogeniser. This dispersion was added to a stirred suspension ofEudragit. The Eudragit suspension was stirred using a mixer. Furtherpurified water was added to provide the coating composition. Sureleasecoating may be used in place of the mixture of Eudragit with talc ormagnesium stearate.

Zafirlukast pellets [Example 7] (400 g) were heated to 24-35° C. in theproduct container of a fluid bed drier equipped with a Wurster column orrotor insert.

The pellets were coated with the coating composition [for exampleEudragit NE30D (200 g) and talc (30 g) with purified water (370 g)] anddried at 24-30° C. to provide coated pellets.

TABLE Coating Suspension Composition: Example: 9 10 11 12 13 14 15 16Eudragit NE30D 15% 10% 10% 10% 10% Talc 10% 5% 5% 5% Magnesium Stearate,USP 5% Surelease 15% 15% 15% Purified Water, USP 75% 85% 85% 85% 85% 85%85% 85% Amount of Coating 120 g 55.6 g 135 g 188 g 55 g 55 g 134 g 188 gSuspension Applied Percent Weight Gain 7.5% 2% 5% 7% 2% 2% 5% 7%Example: 17 18 19 20 21 22 23 24 Eudragit NE30D 5% 5% 2.5% 2.5% 5% 5%Talc 5% 5% 2.5% 2.5% 10% 10% Surelease 25.3% 25.3% Purified Water, USP90.0% 90.0% 95.0% 95.0% 74.7% 74.7% 85.0% 85.0% Amount of Coating 80 g200 g 160 g 400 g 34.5 g 83 g 60 g 140 g Suspension Applied PercentWeight Gain 2% 5% 2% 5% 2% 5% 2% 5%

EXAMPLE 25

Sustained Release Coated Pellets

A composition was prepared in the same manner as in Examples 2-8 withzafirlukast (19.74%), starch (24.29%), confectioners' sugar (5.37%),polyvinylpyrrolidone (1.28%) on sugar spheres (30/35 mesh) (49.36%)using purified water (62.17% of the powder weight).

These pellets (5000 g) were coated, in a manner similar to that ofExamples 9-23, with a coating suspension (35 g) [Surelease (25.0%) andpurified water (75%)]. The coating provided, after heating, coatedpellets with a weight gain of 2%.

In a further experiment, coating suspension (82 g) [Surelease (25.0% inpurified water (85 g)] provided a weight gain of 5%.

What is claimed is:
 1. A dry powder layering process for preparing apharmaceutical composition which comprises a plurality of pellets, eachof said pellets comprising: a) a core; b) a first layer surrounding saidcore which layer contains amorphous zafirlukast substantially free ofother physical forms; and c) a second coating layer which does notcontain zafirlukast; each layer optionally comprising otherpharmaceutically acceptable ingredients, said process comprising thestep of applying in separate feeds (1) amorphous zafirlukast in drypowder form and (2) a binding agent, and each feed optionally addingother pharmaceutically acceptable ingredients to a plurality of cores toform layered pellets, wherein the feed containing the binding agentcommences slightly before the feed containing zafirlukast and endsslightly after the feed containing zafirlukast.
 2. The process accordingto claim 1 wherein the binding agent is water or water in admixture withother solvents.
 3. The process according to claim 1 which comprisesapplying a further binding agent being polyvinylpyrrolidone.
 4. Theprocess according to claim 3, wherein the first layer surrounding thecore comprises polyvinylpyrrolidone in the range 5-30% by weight of theamount of zafirlukast present.
 5. A pharmaceutical composition whichcomprises a plurality of pellets, each of said pellets comprising: a) acore; b) a first layer surrounding said core which layer containsamorphous zafirlukast substantially free of other physical forms; and c)a second coating layer which does not contain zafirlukast; each layeroptionally comprising other pharmaceutically acceptable ingredients,wherein the composition is prepared by a process according to claim 1.6. The pharmaceutical composition according to claim 5, wherein thefirst layer surrounding the core further comprises polyvinylpyrrolidonein the range of 5-30% by weight of the amount of zafirlukast present. 7.The pharmaceutical composition according to claim 5 wherein the secondcoating layer provides sustained release of zafirlukast.
 8. Thepharmaceutical composition according to claim 5 which comprises afurther layer which does not contain zafirlukast and provides sustainedrelease.
 9. The pharmaceutical composition according to claim 5 packagedin sachet, capsule or metered delivery device.
 10. The method oftreating patients in need thereof with a pharmaceutical compositionaccording to claim 5 which composition contains an effective amount ofzafirlukast.